title: Improving efficacy of clinical islet transplantation with iodixanol-based islet purification, thymoglobulin induction, and blockage of IL-1β and TNF-α.
abstract: Poor efficacy is one of the issues for clinical islet transplantation. Recently, we demonstrated that pancreatic ductal preservation significantly improved the success rate of islet isolation; however, two transplants were necessary to achieve insulin independence. In this study, we  introduced iodixanol-based purification, thymoglobulin induction, and double blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression to improve the efficacy of clinical islet transplantation. Nine clinical-grade human pancreata were procured. Pancreatic ductal preservation  was performed using ET-Kyoto solution in all cases. When the isolated islets met the clinical criteria, they were transplanted. We utilized two methods of immunosuppression and anti-inflammation. The first protocol prescribed daclizumab for induction, then sirolimus and tacrolimus to maintain  immunosuppression. The second protocol used thymoglobulin for induction and tacrolimus and mycophenolate mofetil to maintain immunosuppression. Eternacept and anakinra were administered as anti-inflammatory drugs. The total amount of insulin required, HbA1c, and the SUITO index were determined  to analyze and compare the results of transplantation. All isolated islet preparations (9/9) met the criteria for clinical transplantation, and they were transplanted into six type 1 diabetic patients. All patients achieved insulin independence with normal HbA1c levels; however, the first  protocol required two islet infusions (N = 3) and the second protocol only required a single infusion (N = 3). The average SUITO index, at 1 month after a single-donor islet transplantation, was significantly higher in the second protocol (49.6 ± 8.3 vs. 19.3 ±  6.3, p < 0.05). Pancreatic ductal preservation, iodixanol-based purification combined with thymoglobulin induction, and blockage of IL-1β and TNF-α as well as sirolimus-free immunosuppression dramatically improved the efficacy of clinical islet transplantations. This protocol  enabled us to perform successful single-donor islet transplantations. Further large-scale studies are necessary to confirm these results and clarify the mechanism of each component.
authors.affiliation: Baylor All Saints Islet Cell Laboratory, Fort Worth, TX 76104, USA. shinichm@baylorhealth.edu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Morihito
authors.initials: M
authors.lastname: Takita
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Koji
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Daisuke
authors.initials: D
authors.lastname: Chujo
authors.forename: Jeff
authors.initials: J
authors.lastname: SoRelle
authors.forename: Nicholas
authors.initials: N
authors.lastname: Onaca
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
authors.forename: Marlon F
authors.initials: MF
authors.lastname: Levy
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000378:metabolism*; D000077561:Daclizumab; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D014283:Triiodobenzoic Acids / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018124:Receptors, Tumor Necrosis Factor; D014283:Triiodobenzoic Acids; D014409:Tumor Necrosis Factor-alpha; D000077561:Daclizumab; C512542:thymoglobulin; C044834:iodixanol; D000068800:Etanercept; D020123:Sirolimus